rs1057516055

chrM-1661-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000387342.1(MT-TV):n.60A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: MT-TV ENST00000387342.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 9.1
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3 Charcot-Marie-Tooth-(CMT)
• Conservation: PhyloP100: 0.0530

Genes affected

MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)

TRNV (HGNC:):

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP4: Mitotip and hmtvar scores support benign criterium.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNV	TRNV.1	n.60A>G		non_coding_transcript_exon_variant	1/1
RNR2	RNR2.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TV	ENST00000387342.1	n.60A>G		non_coding_transcript_exon_variant	1/1
MT-RNR2	ENST00000387347.2			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0 AC: 1

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56398

Gnomad heteroplasmic AF: 0.000053 AC: 3 AN: 56398

Mitomap

Charcot-Marie-Tooth-(CMT)

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2024

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Oct 23, 2023

The m.1661A>G variant in MT-TV has been reported in two unrelated families (PS4_supporting). Limited phenotypic details are provided in the first reported family (Patient 6 in Bacalhau et al., 2017, PMID: 28027978) however a subsequent publication reported the proband in this family had seizures, hypotonia, developmental delay, elevated blood lactate, and combined deficiency of electron transport chain enzyme activities (PMID: 32715519). The heteroplasmy level and information on family members and/or testing in family members were not reported in this first kindred. The second family reported was a large kindred from the Venezuelan Andes with axonal Charcot-Marie-Tooth (CMT) disease (motor and sensory neuropathy). Muscle weakness, muscle atrophy, and ataxia were also seen in the affected individuals in this family (Fay et al., 2020, PMID: 32715519). Muscle biopsies performed in several individuals showed denervation and reinnervation, in addition to mitochondrial hyperplasia, mildly increased glycogen, and the presence of mitochondrial crystalline arrays. Combined respiratory chain enzyme deficiencies were also seen in affected individuals from this kindred. The variant was present at homoplasmy in blood and/or muscle in both affected and unaffected individuals from this kindred. There are no reported de novo occurrences on this variant to our knowledge. The computational predictor MitoTIP suggests this variant is benign (27.6 percentile; BP4).This variant is present in population databases (MITOMAP: 1/61,168 sequences, AF=0.002%, haplogroup (Hg) H1c; Helix: 2/195,983 (0.001%), also 19 heteroplasmic occurrences, homoplasmic occurrences in Hg I and V, heteroplasmic in multiple haplogroups; and gnomAD v3.1.2: 2/56,398 (0.004%), also three heteroplasmic occurrences (heteroplasmy levels: 10-20%; 20-30%; 90-100%), one in Hg T, one in H, one in B, one in K, one in L3). Given the frequency of this variant, it does not meet PM2 criterion. There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 23, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, BP4 -

Epilepsy;C0424605:Developmental delay;C1853743:Axial hypotonia;CN239816:Hyperlactaemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Center for Neuroscience and Cell Biology, University of Coimbra, Portugal

Nov 21, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	9.1
Hmtvar	Benign	0.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057516055; hg19: chrM-1663;